Quaternary ammonium salt with small molecular weight and preparation method and application thereof

A small molecular weight, quaternary ammonium salt technology, applied in the field of compounds carrying nucleic acid drugs, to achieve the effect of low toxicity and improved release

Active Publication Date: 2017-12-19
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, most of the carrier materials currently studied, after the responsive fracture, the cationic materials or fragments produced can still have strong adsorption with nucleic acid drugs.

Method used

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  • Quaternary ammonium salt with small molecular weight and preparation method and application thereof
  • Quaternary ammonium salt with small molecular weight and preparation method and application thereof
  • Quaternary ammonium salt with small molecular weight and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Embodiment 1: synthetic N, N, N-trimethylcystamine trifluoroacetate

[0047]1) Weigh 200 mg of cystamine dihydrochloride (referred to as cystamine) and dissolve in 10 ml of methanol, and add 386 μl of triethylamine; dissolve 192.5 mg of di-tert-butyl dicarbonate (BOC anhydride) in 2 ml of methanol, gradually Add it dropwise to methanol solution of cystamine dihydrochloride, stir at room temperature for 30 minutes, and evaporate methanol to dryness by rotary evaporation. Continue to add 50ml of sodium dihydrogen phosphate solution (NaH 2 PO 4 , 1M), washed twice with ether to remove the product that both ends are connected to BOC anhydride, using NaOH (1M) to adjust the pH of the solution to 9, extracting with ethyl acetate to obtain the cystamine protected by BOC at one end, rotary steaming The ethyl acetate layer was dried to give a white product (designated cystamine-BOC).

[0048] 2) Weigh 50 mg of the above product, dissolve it in 1 ml of acetonitrile, add 64.6 m...

Embodiment 2

[0053] Embodiment 2: Synthetic N, N, N-trimethylcystamine iodide salt

[0054] (1) Dissolve 500 mg of cystamine dihydrochloride (referred to as cystamine) in 10 ml of methanol, and add 965 μl of triethylamine; react for 30 minutes, dissolve 223 mg of benzyl chloroformate (CBZ) in 2 ml of methanol, Add it dropwise to methanol solution of cystamine dihydrochloride, stir at room temperature, observe the reaction progress by thin-layer chromatography, and evaporate the methanol to dryness after the raw material point disappears. Continue to add hydrochloric acid solution (HCl, 1M), wash twice with ether to remove the product with CBZ anhydride attached to both ends, use NaOH (1M) to adjust the pH of the solution to 9, and extract with ethyl acetate to obtain CBZ protected at one end. Cystamine, and the ethyl acetate layer was evaporated to dryness by rotary evaporation to obtain a white product (referred to as cystamine-CBZ).

[0055] (2) Weigh cystamine-CBZ 39mg, add 64.6mg K 2...

Embodiment 3

[0057] Embodiment 3: synthetic N, N, N-trimethylcystamine chloride salt

[0058] In this example, 1 ml of saturated ethyl acetate (3M) hydrochloric acid was added to remove BOC, reacted at room temperature for 30 minutes, and the solvent was spin-dried, and the rest of the steps were the same as in Example 1 to prepare solid N,N,N-trimethylcystamine chloride Salt.

[0059] The result shows: carry out mass spectrometric characterization for N,N,N-trimethylcystamine iodonium salt-BOC and N,N,N-trimethylcystamine chloride salt in embodiment 3, such as Figure 3-4 shown. Molecular ion peak of N,N,N-trimethylcystamine iodide-BOC ([M+H] + ) is 295.17, and the molecular ion peak of N,N,N-trimethylcystamine chloride ([M+H] + ) is 195.10, which proves that N,N,N-trimethylcystamine chloride has been successfully synthesized.

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Abstract

The invention relates to quaternary ammonium salt, which has a cation structural formula shown in a specification, wherein R1 and R2 are respectively and independently expressed as C2-C4 alkyl, and R3 independently expresses amino, hydroxyl, carboxyl, aldehyde group, mercapto group, hydrazino or succinimido. The invention also relates to a preparation method and an application, the cation structure of the quaternary ammonium salt with small molecular weight contains disulfide bond, which can be decomposed under effect of reduced glutathione in cells, cytotoxicity can be reduced, and the release of nucleic acid medicines can be improved.

Description

technical field [0001] The invention relates to a compound for carrying nucleic acid drugs, in particular to a small molecular weight quaternary ammonium salt and its preparation method and application. Background technique [0002] Gene therapy has broad application prospects in the treatment of diseases caused by human gene defects or abnormalities. However, due to the instability of nucleic acid drugs in the body, easy to be degraded, and difficult to absorb into target cells, the delivery technology of nucleic acid drugs has become a near Research and development hotspots in recent years. [0003] Compared with viral vectors, non-viral vectors have the advantages of easy synthesis, low immunogenicity and high safety, and have good application prospects. They mainly include cationic lipids and cationic polymers, such as cationic liposomes lipofectamine 2000, cationic polymer polyethyleneimine (PEI), polylysine, polyglutamic acid, polyamide-amine dendrimers, polyethylmeth...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C319/24C07C323/25A61K47/18
CPCA61K47/186C07C319/24C07C323/25C07C323/43
Inventor 韩旻刘惠娜林梦婷郭宁宁郭望葳王田田
Owner ZHEJIANG UNIV
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